Type VII collagen (Collagen 7) is the major component of anchoring fibrils, attachment structures within the basement membrane zone (BMZ) between the epidermis and dermis of human skin. Genetic defects in the Collagen 7 gene result in dystrophic epidermolysis bullosa (DEB), diseases characterized by generalized blistering and skin fragility.
Collagen 7 is composed of three identical alpha chains, each consisting of a 145 kDa central collagenous triple-helical segment (TH), flanked by a large globular 145 kDa amino-terminal non-collagenous domain (NC1), and a smaller 34 kDa carboxyl-terminal non-collagenous domain (NC2). Sequence analysis of NC1 reveals multiple submodules with homology to known adhesive molecules, such as cartilage matrix protein (CMP), nine fibronectin type III-like repeats (FNIII), and the A domain of von Willebrand factor (VWF-A). The very adhesive NC1 domain may facilitate binding of Collagen 7 to other BMZ and extracellular matrix components (ECM). These associations may stabilize Collagen 7 molecular aggregations and adhesion of the BMZ to the dermis. Therefore, structural alterations in Collagen 7 are likely to result in functional disruption in its interactions with ECM components and epidermal-dermal disadherance, as seen in DEB.
TGF-β has been shown to bind to various ECM proteins such as fibronectin, type IV collagen and tenascin as well as a number of small interstitial proteoglycans such as biglycan, decorin and fibromodulin. This matrix binding may regulate TGF-beta activities by sequestering TGF-beta into extracellular matrix and inhibiting its fibrotic properties. Fibronectin type III like repeats (FNII) within fibronectin and tenascin are responsible for their binding to TGFβ.
As shown in FIGS. 14A and 14B, patients with RDEB often suffer severe scarring and fibrotic mitten deformities that are characteristic. Aggressive and usually fatal skin cancers develop in areas of scarring and chronic wounds that frequently took the patients' life. These children have a gene defect in the COLA1 gene leading to abnormal type VII collagen, the major component of anchoring fibrils. As electron micrograph of normal human skin in FIG. 14C, these are large structures located that the dermal-epidermal junction and function to hold the epidermis and dermis together. The electron micrograph of RDEB skin in FIG. 14D shows a paucity of anchoring fibrils and clear epidermal-dermal separation.